Hematopoietic stem cells are one of the most sensitive tissues to radiation exposure. Epidemiological studies of atomic bomb survivors in Nagasaki and Hiroshima revealed a radiation dose-response relationship for acute myeloid leukemia, acute lymphoblastic leukemia, and Chronic myelogenous leukemia. In our study of myelodysplastic syndrome (MDS) in Nagasaki, the relative risk was higher in the proximal-exposed group. Additionally, the frequency of chromosome abnormalities associated with poor prognosis was higher in the proximal-exposed group than in the non-exposed group. However, no association between the exposure distance and prognosis was observed. We used next-generation sequencing to analyze the role of genetic abnormalities in the development of MDS. The results indicated that genetic mutations related to DNA methylation pathways, which are frequently observed in de novo MDS, were considerably less frequent in the proximal-exposed than in the distal-exposed group. These results suggest that the pathogenesis of MDS in atomic bomb survivors may be different from that of treatment-related and de novo MDS.

The nervous system is distributed throughout all body organs and unconsciously maintains homeostasis. The peripheral nervous system, which comprises autonomic and sensory nerves, is distributed in the bone marrow, which controls hematopoiesis, and the surrounding bone tissue, which is also closely associated with hematopoiesis regulation. Recent advances in research techniques have revealed that the peripheral nervous system affects normal hematopoiesis, hematopoiesis under stress, and the regulation of hematopoietic aging. The peripheral nervous system also affects the development and progression of malignant tumors, including hematopoietic tumors and normal tissue, making the peripheral nerve regulation a potential new therapeutic target.

Hematopoietic stem cells (HSCs) are defined as cells present in the bone marrow that are capable of both self-renewal and multilineage differentiation. The differentiation pathway from HSCs to mature blood cells and HSC self-renewal and differentiation mechanisms still remain unclear and require further elucidation. However, HSCs are a highly diverse population with analysis limitations at the population level. Moreover, molecular and cell biological single-cell analysis has been attracting tremendous attention recently. Herein, we introduce a cell biological single-cell analysis method (single-cell transplantation and cell lineage tracing experiments using genetic techniques) in the field of HSCs.

Protein production is tightly regulated in cells because the accumulation of un-/misfolded proteins triggers cellular responses, particularly in the endoplasmic reticulum (ER). Recently, several studies have reported the implications of unfolded protein response (UPR) and ER stress in hematopoiesis, particularly in hematopoietic stem cells (HSCs). The majority of HSCs are maintained in a dormant state under physiological conditions in the adult body, and their protein synthesis rate is also maintained at a low level. Once HSC proliferation is activated, the protein synthesis rate is elevated, and therefore, newly synthesized peptides have to be efficiently folded to prevent the induction of UPR. Importantly, UPR can expand the ER capacity that enables increased protein production and eliminates cells accumulating abnormal proteins; thus, blocking the UPR signal could rather be hazardous for the cells. Thus, understanding how protein quality control is properly controlled and developing methods to manipulate the regulatory mechanisms are imperative to maximize the potential role of HSC.

Autoimmune hemolytic anemia (AIHA) is caused by damaged red blood cells due to auto-antibodies targeting its membrane proteins. The heterogeneous group of diseases is divided into two types depending on the thermal amplitude of autoantibodies: warm and cold AIHA. Cold AIHA includes cold agglutin disease and paroxysmal nocturnal hemoglobinuria. AIHA is also divided into primary and secondary AIHA depending on its etiology. Recent advances in understanding the pathogenesis have revealed that AIHA brings not only anemia but also thromboembolic risk or impaired quality of life (QOL). This review describes its pathogenesis, diagnostic approach, and treatment strategies based on the latest information.

The body does not possess an active export system for iron. Therefore, the amount of iron uptake is usually small; iron metabolism in the body should be considered a “semi-closed system.” However, iron needed for erythropoiesis can be lacking in the case of continuous bleeding, and thus, iron deficiency anemia (IDA) would occur. IDA is the most common form of anemia; approximately 70% of anemia is IDA. Therefore, upper and lower endoscopies or gynecological procedures should be used to treat bleeding sites; in addition, the small intestine can now be widely observed and treated by double-balloon and capsule endoscopies. Iron replacement therapy for IDA is also important; however, oral iron administration frequently causes adverse events in the gastrointestinal tract, such as nausea and vomiting, making long-term oral iron administration difficult. Newly approved ferric citrate hydrate causes fewer adverse events for the gastrointestinal tract. For a long time, concerning intravenous (IV) iron formulation, saccharated ferric iron oxide has been the only available IV iron formulation in Japan. However, ferric carboxymaltose was recently approved, and administration at a dose of 500 mg/day can achieve a certain iron replacement with less administration. Thus, more effective treatment for patients with IDA might be achieved by these new procedures as well as oral and IV iron preparations.

In 2008, the World Health Organization proposed a provisional entity of childhood myelodysplastic syndrome (MDS) without a blasts increase, which was referred to as the refractory cytopenia of childhood (RCC). We performed a central review of bone marrow morphology in 252 children with acquired bone marrow failure syndromes to clarify the clinical relevance of the RCC. The RCC was divided two categories, namely, RCC without multilineage dysplasia (MLD) and RCC with MLD, which is similar to MDS with MLD in adult MDS. Furthermore, the clinical outcomes were investigated for cases diagnosed with aplastic anemia, RCC without MLD, and RCC with MLD. The response rates to immunosuppressive therapy and the incidence of the development of the new chromosomal aberration did not significantly differ among the three groups. The RCC with MLD can be adopted in childhood MDS since children with this condition exhibited a frequent chromosomal aberration at the time of diagnosis and a high frequency of secondary graft failure after a hematopoietic cell transplantation.

Similar with myelodysplastic syndromes (MDS), aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are the major bone marrow failure syndromes. Approximately 10-20% of patients with AA/PNH present with transformation into MDS. Clonal hematopoiesis in AA/PNH affected by karyotypic abnormalities and genetic mutations should be discriminated from MDS clone, which is sometimes difficult due to shared genetic events among these diseases. In patients with AA/PNH, clones with UPD6p and PIGA mutations are selected under autoimmune pressure, and those with DNMT3A, ASXL1, and TET2 mutations originated from clonal hematopoiesis of indeterminate potential (CHIP) frequently identified in elderly healthy individuals. In patients with cytopenia, a single CHIP mutation is insufficient for MDS presentation. However, TP53 and U2AF1 mutations, which are not in the list of typical CHIP mutations, are observed in patients with AA with future MDS transformation. Therefore, clonal hematopoiesis in AA/PNH, partially overlapping the MDS clone, is caused by autoimmunity and originates from CHIP, demonstrating distinct genetic profiles.

In the bone marrow (BM) microenvironment, acute myeloid leukemia (AML) cells constantly regulate their metabolic state based on extracellular signaling and nutrient availability by making “decisions,” such as quiescence, proliferation, and differentiation. AML cells survive by meeting the biochemical demands of increased cell proliferation and continually adapting to changes in nutrient and oxygen availability. In addition, changes in the metabolism of amino acids, which are intermediate metabolites that fuel multiple biosynthetic pathways, as well as protein components, are another modality for meeting these demands. AML cells rewire metabolic pathways to adapt to increased nutritional demands for energy, reduced equivalents, and cell biosynthesis in the BM microenvironment. Furthermore, BM stromal cells and adipocytes play a role in preventing nutrient starvation-induced apoptosis of AML cells. Therefore, targeting metabolic abnormalities in AML cells is a promising novel therapeutic approach. Thus, this review describes the metabolic and molecular mechanisms of mitochondrial oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism in AML cells under the BM microenvironment.

The landscape of acute myeloid leukemia treatment has changed dramatically over the past decade. In Japan, three novel molecularly targeted agents have been approved and rapidly changing the paradigm of AML therapy. However, as the clinical experience of these novel drugs accumulate, various resistance mechanisms have started to emerge. Here, we discuss the mechanism of action and resistance of the three recently approved drugs, FLT3 inhibitor, IDH inhibitor, and BCL2 inhibitor.

Malignant lymphomas are a group of heterogeneous lymphoid malignancies, consisting of over 70 subtypes, which are classified according to their cell of origin. Classically, disease classification has been based on cellular morphology and immunophenotype. Due to the advancement of next-generation sequencing (NGS) technology, many comprehensive genomic studies have clarified the landscape of somatic alterations in these lymphomas, which has drastically improved our understanding of their molecular pathogenesis. Consequently, a new framework has been proposed for disease classification based on such somatic alterations and/or gene expression characteristic of each lymphoma subtype. Additionally, the results from the genomic studies have also established an important basis for the development of new targeted therapies and prognostic biomarkers. In the future, NGS-based gene panels will be covered by health insurance, and cancer precision medicine is expected to become more prevalent in this field. This paper outlines the analytical methods used in genomic studies by primarily focusing on NGS technology, and describes the results of major genomic and single-cell studies for various subtypes of malignant lymphoma.

The novel coronavirus disease 2019 (COVID-19) is caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of mortality and morbidity with COVID-19 due to severe immune dysfunction. Recombinant adenovirus vector-based vaccine, such as AstraZeneca ChAdOx1, and mRNA-based vaccines, such as Pfizer BNT162b2 and Moderna mRNA-1273 have been used in Japan. COVID-19 vaccine administration to HSCT recipients was reported to result in a 68-96.5% seroconversion for the spike protein. Factors associated with the absence of humoral responses were the time-interval from HSCT to vaccination, absolute lymphocyte count, systemic immunosuppressive treatments, graft versus host disease (GVHD), B-cell count, and hypogammaglobulinemia. New onset and exacerbation of chronic GVHD have been reported as an adverse events associated with vaccination. COVID-19 vaccination of HSCT recipients is relatively safe, and recipients should be vaccinated against COVID-19 6 months after transplantation. In the future, it is necessary to consider passive immunotherapy for HSCT patients who do not benefit from COVID1-19 vaccination.

Acute myeloid leukemia (AML) is a heterogeneous cell population comprising genetically diverse sub-clones with significant differences in properties that vary from one patient to another. Since AML properties are similar to those of hematopoietic stem and myeloid cells, bone marrow as an organ responsible for the survival of AML-initiating cells has been proposed to be able to cause relapse following chemotherapy. Therefore, establishing in vivo experimental systems is critical for understanding the properties of AML cells and developing therapeutic strategies. In this review, the history, advantages, and disadvantages of mouse leukemia models wherein mouse cells are transformed by oncogenic events, including xenograft mice in which human AML cells are transplanted into immunodeficient mice, were introduced. Following which I described the development of chimeric antigen receptor cell therapy using human cytokines expressing the AML xenograft mice.

Since the discovery of the JAK2V617F, MPL gene, and Calreticulin gene mutations, remarkable changes have occurred in the identification of the pathology of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnostic criteria of polycythemia vera, essential thrombocythemia, and primary myelofibrosis in the world health organization classification systems have also been amended to include these driver gene mutations. Additionally, treatment algorithms for each disease have been reviewed. Following these changes, real world data form several countries based on national surveys have been reported. In Japan, the Japanese Society of Hematology has conducted a prospective study, named the JSH-MPN-15 study, to investigate the overall survival and risk factors of patients with MPNs. Furthermore, the retrospective JSH-MPN-R18 study was conducted and the results have been coming out. In this lecture, the results of these studies will be discussed.

The introduction of tyrosine kinase inhibitors (TKIs) as treatment for patients with chronic myeloid leukemia (CML) has dramatically improved the outcomes. The life expectancy of patients with CML is now comparable to that of the general population. Although the median age of onset of CML is around 60 years, it can also occur in children, adolescents, and young adults. The excellent disease control gives young patients a hope of childbearing. However, TKIs may have teratogenic potentials in the issue of fertility and pregnancy. One possible scenario is to discontinue TKI treatment for conception and pregnancy because treatment-free remission (TFR) is a realistic option for patients with CML in sustained deep molecular remission. Conversely, pregnancy occurs in patients who are ineligible for TFR or who have active CML. Therefore, several treatment strategies should be prepared from the viewpoint of the situation of pregnancy in patients with CML.

Several novel myelodysplastic syndromes (MDS) treatment drugs are being developed, and luspatercept and oral hypomethylating medicines have already been licensed in the United States and other countries. Luspatercept is a ligand trap that inhibits SMAD2/3 signals by combining the extracellular domain of the activin type IIA receptor with the human immunoglobulin G1 Fc domain. In the phase 2 study for low-risk MDS, the hematological improvement-erythroid (HI-E) was found in 63% of patients, and in the phase 3 study for transfusion-dependent low-risk MDS with ring sideroblasts, 38% of patients achieved transfusion independence. A combination of oral decitabine with oral cedazuridine, an inhibitor of cytidine deaminase, which metabolizes decitabine, demonstrated pharmacological equivalence with intravenous decitabine and has overall response rates of 60% and 43% for high-risk MDS in phase 2 and 3 trials, respectively. Furthermore, oral azacitidine and its combination with oral cedazuridine have been under development.

Vascular diseases are a feature of myeloproliferative neoplasms (MPNs) with a driver mutation, such as JAK2V617F. There is growing evidence that clonal hematopoiesis with JAK2V617F (JAK2V617F-CH) is often complicated with vascular diseases, even in the absence of MPN onset. Such vascular diseases associated with the MPN driver mutation include arterial/venous thrombosis, atherosclerotic coronary artery disease and aortic aneurysm, and pulmonary hypertension. Murine studies have recently revealed mechanisms by which hematopoietic cells activated by the MPN driver mutation may promote thrombosis and vascular remodeling in deep vein stenosis, atherosclerosis, and pulmonary hypertension models. Furthermore, MPN driver mutations mediate various downstream molecules of JAK-STAT activation in neutrophils and macrophages, such as inflammatory cytokines, which may be candidates for preventing and treating vascular diseases in MPNs and JAK2V617F-CH.

Inherited bone marrow failure syndrome (IBMFS) is a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and an increased risk of malignancy. The p53 tumor suppressor protein is a transcription factor activated in response to various cellular stresses and induces genes involved in apoptosis, cell cycle arrest, and DNA repair. Several lines of evidence suggest that p53 activation is central to the pathogenesis of IBMFS. We discovered germline TP53 activating mutations in IBMFS cases mimicking Diamond-Blackfan anemia using whole-exome sequencing. These cases were recognized as having a novel disorder, germline TP53 activation syndrome (bone marrow failure syndrome 5; OMIN). Recently, additional cases with the same TP53 mutations were reported, further clarifying the phenotype of this disease. This discovery confirms the hypothesis that p53 activation causes IBMFS. This review focuses on this novel IBMFS and discusses the link between p53 hyperactivation and IBMFS.

R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been used as the standard treatment regimen for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), since the introduction of rituximab in the early 2000s. Recently, polatuzumab vedotin and anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy have been introduced as potential treatment options for relapsed or refractory DLBCL. The effectiveness of polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone for newly diagnosed CD20-positive DLBCL, except for the low-risk group of the international prognostic index, was reported in 2022. Bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab, anti-CD19 antibody drug tafasitamab combined with lenalidomide, CD19 antibody drug conjugate loncastuximab tesirine, oral selective inhibitor of nuclear export selinexor, and several new agents have been investigated for DLBCL. For non-germinal center B-cell type DLBCL, R-CHOP combined with acalabrutinib is being evaluated. This review summarizes the current standard of care for DLBCL and outlines the recently introduced therapeutic agents or those that are under development in Japan.

Follicular lymphoma (FL) is the most common type of low-grade, non-Hodgkin lymphoma. Although FL is generally a chemo-sensitive disease, current treatment strategies cannot cure patients with advanced-stage FL. Therefore, FL patients experience remission and relapse many times and generally have a long clinical course. The treatment goals for FL focus on improving subjective symptoms, recovery of cytopenia, and improvement in the quality of life. Careful watch and wait is an important treatment for asymptomatic FL with a low tumor burden. Rituximab monotherapy is also an important option for patients who have mild symptoms. The standard treatment for FL with a high tumor burden includes a combination of anti-CD20 antibodies, like rituximab or obinutuzumab, and chemotherapy like bendamustine and CHOP. The group with poor prognosis FL, such as POD24, should be considered for high-intensity therapies that include hematopoietic cell transplantation. In recent years, the development of molecular targeted therapies for recurrent FL has been vigorously promoted. Recently, lenalidomide and tazemetostat have been approved in Japan. This manuscript outlines the treatment strategy for untreated and relapsed FL and discusses future issues.

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin’s lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma (DLBCL) histology and is highly prevelant in elderly patients. Whole brain radiotherapy (WBRT) does not provide considerable remission; rather it is highly involved in the development of leukoencephalopathy with delayed neurotoxicity, notably in elderly patients. Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity. Comprehensive genetic analyses have revealed high rates of oncogenic mutations in CD79B and MYD88 genes, the hallmarks for MCD/C5 subtype of DLBCL, leading to constitutive activation of NF-κB signaling pathways in PCNSL. Bruton’s tyrosine kinase (BTK), an intermediate kinase downstream to CD79B/MYD88, has emerged as a promising therapeutic target. Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.

Malignant lymphomas are a group of diseases in which epigenomic abnormalities are fundamental to the pathogenesis and pathophysiology and are characterized by a high frequency of abnormalities in DNA methylation regulators and histone modifiers. These epigenomic abnormalities directly amplify malignant clones. They also originated from a cell lineage differentiated from hematopoietic stem cells through epigenomic changes. These characteristics are associated with their high affinity for epigenomic therapies. Hematology has been a leader in the basic, clinical, and drug discovery areas of disease epigenetics. However, the epigenomic regulation is generally recognized as a complex system, and gaps are observed between basic and clinical studies. To overview the status and importance of “epigenomic abnormalities in malignant lymphoma,” this review first summarizes the concept and essential importance of the epigenome and then outlines the current status and future perspective of epigenomic abnormalities in malignant lymphomas.

It is well documented that multiple myeloma (MM) originates in a single plasma cell transformed by chromosome 14q translocations or chromosomal hyperdiploidy and evolves with the accumulation of point mutations of driver genes and/or cytogenetic abnormalities. Furthermore, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at premalignant stages and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes, including drug sensitivities. Generally, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs although could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to the microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ∼20% of MM evolve neutrally in the context of strong oncogenic drivers, including high-risk IgH translocations, and are relatively resistant to IMiDs. Treatment strategies considering the genomic landscape and the pattern of clonal evolution may further improve the treatment outcome of MM.

Treatment outcomes for multiple myeloma (MM) have improved due to the introduction of autologous stem cell transplantation and novel drugs. However, many patients develop resistance to existing therapies; hence, novel treatment strategies for these patients must be established. Therapeutic antibodies, including daratumumab and isatuximab targeting CD38 and elotuzumab targeting SLAMF7, have been introduced as immunotherapies for MM. These antibodies exert cytotoxic effects on myeloma cells through the activation of effectors such as natural killer cells and complement, and induction of phagocytosis by macrophages. Suppressed anti-tumor immunity may be related to acquisition of drug resistance by myeloma cells in patients with MM. It has been reported that the effect of therapeutic antibodies is through the stimulation of anti-tumor immunity. Thus, as each therapeutic antibody displays its own mechanism of action, therapy based on this mechanism of action should be introduced. Furthermore, chimeric antigen receptor (CAR) T-cell therapy, antibody drug conjugates (ADC), and bispecific antibodies (BsAbs) are gradually being introduced as novel immunotherapies for MM. CAR T-cells with high proliferation levels and persistence in recipients to improve the duration of therapeutic response are currently being developed.

Several types of nonhematopoietic cells, including mesenchymal stem or progenitor cells, mature mesenchymal cells, and endothelial cells, and mature hematopoietic cells such as monocytes, macrophages, NK cells, T cells, and B cells regulate the proliferation and survival of myeloma cells. The cell functions adjacent to myeloma cells is specialized by the location of these cells, called a niche. This review focuses on the role and interaction of cellular components of the myeloma-specific niche revealed by studies that utilized the recently developed experimental techniques of single-cell RNA sequencing and high-parameter cytometry. In the myeloma niche, immune cells and mesenchymal cells regulate tumor proliferation. Bone marrow inflammation induced by multiple myeloma, tumor cells, mesenchymal stromal cells, and immune cells interact, results in the dysregulation of anti-tumor immunity. This complex network could affect tumorigenesis, disease progression, and treatment resistance of multiple myeloma.

At diagnosis, approximately 40% of patients with multiple myeloma are older than 75 years. Thus, treatments for multiple myeloma should take into consideration the following factors: 1) disease-related factors, such as chromosomal abnormalities and speed of progression; 2) therapy-related factors, such as drug resistance and toxicity; and 3) patient-specific factors, such as age, organ dysfunction, and availability of family support. Moreover, with the development of novel therapeutic agents, including antibodies, overcoming the high risk of disease-related factors, even in older patients, is becoming possible by attaining favorable responses to treatment. However, the premise is to continue highly effective treatments from an early stage and maximize the performance of the selected treatments. Therefore, treatments must be provided regularly while adjusting its intensity and duration. Furthermore, for older patients with high frailty, improving and maintaining the health-related quality of life may be necessary. Hence, various treatments and frailty assessments here are described here, including therapeutic ingenuity and supportive care strategies for developing individualized treatments for transplant-ineligible patients.

Chimeric antigen receptor (CAR) T-cell therapy has become the standard of care for some B-cell malignancies due to its high antitumor efficacy. However, adverse events specific to CAR T-cell therapy, such as cytokine release syndrome (CRS), are frequently observed. Typical clinical manifestations of CRS include hyperthermia, hypotension, hypoxemia, and increased vascular permeability. Coagulopathy may also be observed along with to the typical symptoms of CRS. Previous studies, including ours, have revealed that the increase in interleukin-6 levels associated with CRS promotes production of plasminogen activator inhibitor-1 from the vascular endothelium, resulting in suppressed fibrinolysis and hypercoagulability and an exhaustible decrease in fibrinogen. Continuous monitoring of coagulation parameters is necessary during CAR T-cell therapy, and adequate provision of fresh-frozen plasma or cryoprecipitate is recommended if the patient is evaluated to be at high risk for severe CRS.

Replacement therapy is the basic treatment for hemophilia by infusing deficient clotting factors, including replacement therapy for prophylaxis (i.e., prevention of breakthrough bleeding for physical activity), episodic replacement therapy, replacement therapy during and after procedures and surgery, and replacement therapy for physical activity, each administered at doses and intervals appropriate for the purpose and the product used. Although emicizumab is increasingly used for prophylaxis in severe hemophilia A, the combination of replacement therapy is necessary, especially during severe bleeding, highly invasive procedures, and major surgery. Furthermore, the usual APTT measurements cannot be used for monitoring the replacement therapy and detecting the presence of inhibitors while patients are receiving emicizumab. Hemostatic management of patients with inhibitors should be implemented based on the purpose of the therapy, the latest inhibitor titer, and the clinical response to the product, with the choice of inhibitor neutralization or bypass agent therapy. When bypassing agents are used in patients with hemophilia A with emicizumab inhibitor during and after bleeding, procedures, and surgery, the choice of agent and dose adjustment should be made with attention to thrombotic complications.

Hereditary thrombophilia is a condition in which individuals are susceptible to the formation of thrombi due to a hereditary deficiency in the anticoagulant factors antithrombin (AT), protein C, or protein S. The recommendations for peripartum management are as follows: 1) For women with acute venous thromboembolism (VTE) during pregnancy, anticoagulant therapy with a therapeutic dose of unfractionated heparin (UFH) is recommended; 2) For women with a history of VTE, a prophylactic dose of UFH is suggested during pregnancy; 3) For those with AT deficiency, supplementation with an AT preparation in addition to UFH is suggested; 4) For women with no history of VTE, anticoagulant therapy during pregnancy is considered for each thrombophilia type; 5) When anticoagulant therapy consisting of a prophylactic dose of UFH is administered during pregnancy, injection is discontinued with the onset of labor pains in cases of vaginal delivery and 6 hours before the start of delivery in cases of planned delivery or cesarean section; 6) In cases of AT deficiency, regardless of the thrombophilia type, supplementation with AT before and after delivery is suggested; 7) For women with thrombophilia and a history of VTE and for those who receive anticoagulant therapy during pregnancy, postpartum anticoagulant therapy is recommended.

The levels of anti-platelet factor 4 (PF4) antibodies, also known as anti-PF4 or heparin complex antibodies, are used to diagnose heparin-induced thrombocytopenia (HIT). In HIT, anti-PF4 antibodies induced by heparin exposure cause thrombocytopenia and thrombosis. However, anti-PF4 antibodies were recently reported to be associated with the development of fatal vaccine-induced immune thrombotic thrombocytopenia (VITT) after adenoviral vector vaccination for coronavirus disease 2019. HIT and VITT are caused by anti-PF4 antibodies and have similar pathological conditions. However, the severity of these conditions differs and the detection sensitivity of their antibodies varies depending on the assays used. Herein, we review HIT and VITT associated with anti-PF4 antibodies.

FMS-like tyrosine kinase 3 (FLT3) mutations are observed in 25-30% of patients with acute myeloid leukemia (AML). Due to poor prognosis associated with FLT3-mutated AML, allogeneic hematopoietic transplantation is commonly performed to induce remission. With the availability of active FLT3 inhibitors and improvement in transplants techniques, the outcomes of AML have improved drastically. The results of many clinical trials have shown that FLT3 inhibitors in combination with chemotherapy and post-transplant maintenance therapy are most effective for AML. Furthermore, these developments have opened up the possibility of transplantation for elderly patients in whom transplantation is difficult. Here, we discuss the optimal approach for treating FLT3-mutated AML using FLT3 inhibitors, allogenic transplantation, and post-transplant maintenance therapy.

Remarkable progress has been made in the field of myelofibrosis recently. Along with the use of driver gene mutations for diagnosis of myelofibrosis, non-driver gene mutations that affect its prognosis have also been identified, and new prognostic models based on them have been proposed. Furthermore, several important findings have been reported across diverse research fields, such as determining the appropriate modality for reducing splenomegaly before transplantation either by splenectomy or drug therapy, pre-transplant conditioning and donor selection, and long-term follow-up after transplantation. However, due to the relative rarity of myelofibrosis, it is difficult to keep up with the latest findings and develop the best clinical treatment regimens for patients. The purpose of this study is to summarize the current status and recent findings in transplantation therapy for myelofibrosis and to identify the challenges faced during treatment.

Graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-SCT). Recent advances in understanding the GVHD pathophysiology promoted development of novel therapeutic agents for GVHD. In acute GVHD, emerging evidence suggested that it targets tissue stem cells in the skin, liver, and gut, resulting in treatment refractoriness. Furthermore, antimicrobial peptide deficiency, nutritional status alteration of the gut microbiota, and antibiotic administration lead to gut dysbiosis, which is related to GVHD onset and treatment-related mortality after allo-SCT. In this review, recent advances in understanding the GVHD pathophysiology are summarized, and novel agents for the treatment and prophylaxis of acute and chronic GVHD are introduced.

Invasive fungal infections are frequently observed in patients with hematological malignancies. Thus, monitoring the immunosuppressive factors in each patient, such as neutropenia, mucosal injury, steroid consumption, cellular and humoral immunodeficiencies, etc., is important to establish an appropriate antifungal strategy. Additionally, prophylactic approaches should be planned considering the risk of fungal infection, and early clinical tests should be required in patients with persistent fever or other clinical manifestations for the timely diagnosis of invasive fungal infection. Antifungal profile, adverse effects, and clinical purposes, such as prophylaxis, empiric, preemptive, and target therapies, should be considered in antifungal agent selection.

The efficacy of T-cell therapy depends on the maintenance of antigen specificity, memory phenotype, longterm viability, and proliferative capacity of T cells in vivo. Personalized autologous T-cell therapies pose a few manufacturing challenges, in terms of quality, and supply stability. Recently, it has become possible to derive CD8 killer T cells from induced pluripotent stem cells (iPSCs) and develop CAR-CD8 killer T cells from allogeneic iPSCs. This article reviews CD8 killer T-cell induction from iPSCs, attempts to enhance process safety and reliability, and discusses the use of gene-editing technology for reducing allogeneic antigenicity.

Chimeric antigen receptor (CAR)-engineered T-cell therapy against B-cell malignancies and multiple myeloma was recently introduced for clinical use. However, the efficacy of CAR-T cell therapy is not durable in most patients, warranting the development of CAR-T cells with additional genetic modification or engineering of synthetic molecules to enhance their functions. This review will provide an overview of the molecular mechanisms underlying the functional alteration of T cells, especially transcriptional networks associated with memory formation and T cell exhaustion. In addition, methods to rationally improve CAR-T cell functions based on these mechanistic insights will be discussed.

Based on the progress of gene-modification technologies, bispecific antibodies that possess antigen-binding sites with two different specificities have been developed. After the success of blinatumomab for treating refractory B-cell leukemia, series of clinical trials using bispecific antibodies for relapsed and refractory hematological malignancies are being conducted. Several bispecific antibodies target an antigen expressed by tumor cells and the CD3 molecule where binding of bispecific antibodies can generate artificial immunological synapses between tumor cells and human T cells. Therefore, fine tuning of binding affinity and/or structural conformation concomitant with bispecific antibodies may be required to induce antitumor effects and regulate immune-related adverse events, such as cytokine release syndrome. In the future, combination therapy of conventional chemotherapy and/or allogeneic stem-cell transplantation with bispecific antibody therapy will be necessary. Furthermore, molecular target therapy with bispecific antibody therapy is expected to pave the way for next-generation target therapy, resulting in the development of a further effective and safe treatment strategy for hematological malignancies.

Epstein-Barr virus (EBV)-associated lymphomas are common in Asia and exhibit a poor prognosis. As EBV antigens LMP1 and LMP2 are often expressed in EBV-associated lymphomas, these lymphomas should be a good target for antigen-specific cytotoxic T lymphocyte (CTL) therapy. However, CTLs continuously exposed to viral or tumor antigens often become exhausted. Antigen-specific CTLs generated from induced pluripotent stem cells are functionally rejuvenated, showing a strong antitumor effect on EBV-associated lymphomas and persistence in vivo. For feasible “off-the-shelf” therapy, we generated allogeneic EBV-specific CTLs in the cell processing center and prepared them for actual use in clinical settings.

Pediatric Hodgkin lymphoma (HL) is a malignant disease that arises from lymphoid reticulum cells, which can metastasize to the spleen, liver, and bone marrow, including the lymph nodes. Classic HL is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg (HRS) cell proliferation. Its symptoms include fever, night sweats, weight loss, itching, splenomegaly, and hepatomegaly, along with painless lymphadenopathy. Although HL has long achieved a high cure rate, late complications such as cardiac complications, infertility, and secondary cancers still pose a threat. The current treatment standard includes a combination of multiagent chemotherapy and low-dose radiation therapy, and attempts have been made to establish a regimen that omits radiation therapy in patients who respond well to initial therapy. The introduction of new molecular-targeted agents is expected to result in further treatment reduction.

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10%-15% of pediatric ALL, and its frequency increases during the adolescent and young adult (AYA) periods. The improvements in pediatric T-ALL outcomes have been achieved through the treatment intensification strategies addressing the cranial radiotherapy omission issue. Furthermore, pediatric-inspired regimens have been adopted for AYA patients with T-ALL, improving outcomes. In Japan, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-T11/JALSG T-ALL-211-U trial has been conducted for newly diagnosed patients with T-ALL aged <25 years and has been shown to have excellent outcomes. While early T cell precursor ALL is not an obvious poor prognostic factor in recent treatment strategies for pediatric T-ALL, the minimal residual disease (MRD) has been recognized as the most reliable prognostic indicator. Therefore, MRD is now widely used in T-ALL clinical trials for risk stratification and stem cell transplantation indications. Further progress in the novel therapeutic approaches can potentially improve the outcomes of pediatric and AYA patients with T-ALL.

Patient-derived xenograft (PDX) models have gained attention due to their wide applications in basic research and drug development, and due to the increase in requirements for pathological analysis and anticancer drug evaluation. The development of immunodeficient mouse strains with high-level engraftment of normal and diseased cells has contributed to the considerable progress in understanding the human pathophysiology. The PDX model is one of the most important tools to bridge the gap between traditional animal models and the clinical trials. PDX not only recapitulates human disease in vivo, but also multiplies the tumor cells. Therefore, efforts were made internationally to develop a PDX bank for leukemias and solid tumors for future research and experimentation. PDX might be an ideal model to simulate actual human diseases for cancer research; however, some challenges still persist. Thus, this review aimed to summarize the developmental history of immune-deficient mice, the efforts of overcoming PDX limitations, PDX model applications for preclinical research, and the current attempts to establish domestic leukemia PDX bank in Japan.

In clinical research, the term “conflict of interest” appears quiet frequently. Conflict of interest does not always result in research misconduct, nor is it always an issue. Conflict of interest rules differ depending on the type and stage of research, and researchers are expected to choose and follow them appropriately. In this paper, we review the fundamental concept of conflict of interest management in clinical research and the importance of conflict of interest management, and then organize the various rules based on the type and stage of research. Furthermore, the key points for effective conflict of interest management that researchers should be aware of are summarized.